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Article ; Online: Tumor-specific T-cell memory: clearing the regulatory T-cell hurdle.

Côté, Anik L / Usherwood, Edward J / Turk, Mary Jo

2008 Volume 68, Issue 6, Page(s) 1614–1617

Abstract: Antitumor immune responses can be stimulated by interfering with regulatory T-cell (T(reg)) function. However, this effect is short lived unless T-cell memory to tumor antigens can be generated. Our recent studies show that T(reg) cells not only limit ... ...

Abstract	Antitumor immune responses can be stimulated by interfering with regulatory T-cell (T(reg)) function. However, this effect is short lived unless T-cell memory to tumor antigens can be generated. Our recent studies show that T(reg) cells not only limit primary responses to tumor/self-antigens in tumor-bearing hosts but also prevent the natural generation of T-cell memory to such antigens. Here, we discuss the role of T(reg) cells in suppressing T-cell memory after surgical excision of tumors and the potential clinical benefits of overcoming this suppression.
MeSH term(s)	Animals ; Antigens, Neoplasm/immunology ; Humans ; Immunologic Memory ; Melanoma, Experimental/immunology ; Melanoma, Experimental/pathology ; Melanoma, Experimental/surgery ; Mice ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/surgery ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Antigens, Neoplasm
Language	English
Publishing date	2008-03-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-07-6012
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Article ; Online: CXCR4 and matrix metalloproteinase-1 are elevated in breast carcinoma-associated fibroblasts and in normal mammary fibroblasts exposed to factors secreted by breast cancer cells.

Eck, Sarah M / Côté, Anik L / Winkelman, William D / Brinckerhoff, Constance E

Molecular cancer research : MCR

2009 Volume 7, Issue 7, Page(s) 1033–1044

Abstract: The complex molecular communications that occur between neoplastic and stromal cells within the tumor microenvironment play an integral role in breast cancer pathogenesis. Carcinoma-associated fibroblasts (CAF) produce tumor-enhancing factors and have ... ...

Abstract	The complex molecular communications that occur between neoplastic and stromal cells within the tumor microenvironment play an integral role in breast cancer pathogenesis. Carcinoma-associated fibroblasts (CAF) produce tumor-enhancing factors and have been strongly implicated in breast cancer development. Similar to the way in which tumors have been compared with "wounds that never heal," CAFs have been equated to activated fibroblasts, which are present in inflammatory environments, in which they aid in wound healing through tissue remodeling and repair. Matrix metalloproteinase-1 (MMP-1) and G protein-coupled receptor, CXCR4, are elevated in these activated fibroblasts, in which they facilitate angiogenesis and matrix degradation, processes that are also vital to breast cancer metastasis. In this study, we investigated MMP-1 and CXCR4 expression in normal human mammary fibroblasts (HMF) exposed to soluble breast cancer factors. Historically, elevated CXCR4 expression is associated with breast cancer cells. However, we show that soluble factors secreted by SUM102 breast cancer cells stimulated the expression of MMP-1 and CXCR4 in HMFs. As a result, these stromal cells acquired an invasive and migratory phenotype. To confirm the clinical relevancy of our findings, we analyzed CAFs obtained from primary breast cancers. These cells also displayed elevated MMP-1 and CXCR4 levels compared with counterpart fibroblasts, and were more invasive and migratory. Together, our data suggest that soluble breast cancer factors initiate the transdifferentiation of normal HMFs to tumor-promoting CAFs, and that through the induction of MMP-1 and CXCR4 levels, these cells exhibit an invasive and migratory phenotype.
MeSH term(s)	Animals ; Breast/cytology ; Breast/enzymology ; Breast/metabolism ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Growth Processes/physiology ; Cell Movement/physiology ; Collagen Type I/metabolism ; Female ; Fibroblasts/drug effects ; Fibroblasts/enzymology ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Gene Expression ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism ; Intercellular Signaling Peptides and Proteins/pharmacology ; Interleukin-8/metabolism ; Matrix Metalloproteinase 1/biosynthesis ; Matrix Metalloproteinase 1/genetics ; Matrix Metalloproteinase 1/metabolism ; Mice ; RNA, Messenger/biosynthesis ; RNA, Messenger/genetics ; Receptors, CXCR4/biosynthesis ; Receptors, CXCR4/genetics ; Receptors, CXCR4/metabolism ; Signal Transduction
Chemical Substances	CXCR4 protein, human ; CXCR4 protein, mouse ; Collagen Type I ; Intercellular Signaling Peptides and Proteins ; Interleukin-8 ; RNA, Messenger ; Receptors, CXCR4 ; Matrix Metalloproteinase 1 (EC 3.4.24.7)
Language	English
Publishing date	2009-07-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2098788-2
ISSN	1557-3125 ; 1541-7786
ISSN (online)	1557-3125
ISSN	1541-7786
DOI	10.1158/1541-7786.MCR-09-0015
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Article ; Online: Protective CD8 memory T cell responses to mouse melanoma are generated in the absence of CD4 T cell help.

Côté, Anik L / Byrne, Katelyn T / Steinberg, Shannon M / Zhang, Peisheng / Turk, Mary Jo

PloS one

2011 Volume 6, Issue 10, Page(s) e26491

Abstract: Background: We have previously demonstrated that temporary depletion of CD4 T cells in mice with progressive B16 melanoma, followed by surgical tumor excision, induces protective memory CD8 T cell responses to melanoma/melanocyte antigens. We also ... ...

Abstract	Background: We have previously demonstrated that temporary depletion of CD4 T cells in mice with progressive B16 melanoma, followed by surgical tumor excision, induces protective memory CD8 T cell responses to melanoma/melanocyte antigens. We also showed that persistence of these CD8 T cells is supported, in an antigen-dependent fashion, by concurrent autoimmune melanocyte destruction. Herein we explore the requirement of CD4 T cell help in priming and maintaining this protective CD8 T cell response to melanoma. Methodology and principal findings: To induce melanoma/melanocyte antigen-specific CD8 T cells, B16 tumor bearing mice were depleted of regulatory T cells (T(reg)) by either temporary, or long-term continuous treatment with anti-CD4 (mAb clone GK1.5). Total depletion of CD4 T cells led to significant priming of IFN-γ-producing CD8 T cell responses to TRP-2 and gp100. Surprisingly, treatment with anti-CD25 (mAb clone PC61), to specifically deplete T(reg) cells while leaving help intact, was ineffective at priming CD8 T cells. Thirty to sixty days after primary tumors were surgically excised, mice completely lacking CD4 T cell help developed autoimmune vitiligo, and maintained antigen-specific memory CD8 T cell responses that were highly effective at producing cytokines (IFN-γ, TNF-α, and IL-2). Mice lacking total CD4 T cell help also mounted protection against re-challenge with B16 melanoma sixty days after primary tumor excision. Conclusions and significance: This work establishes that CD4 T cell help is dispensable for the generation of protective memory T cell responses to melanoma. Our findings support further use of CD4 T cell depletion therapy for inducing long-lived immunity to cancer.
MeSH term(s)	Animals ; Antigen Presentation ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cytokines/biosynthesis ; Immunologic Memory/immunology ; Melanoma, Experimental/immunology ; Mice ; T-Lymphocytes/immunology
Chemical Substances	Cytokines
Language	English
Publishing date	2011-10-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0026491
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Article ; Online: Immune modulation effects of concomitant temozolomide and radiation therapy on peripheral blood mononuclear cells in patients with glioblastoma multiforme.

Fadul, Camilo E / Fisher, Jan L / Gui, Jiang / Hampton, Thomas H / Côté, Anik L / Ernstoff, Marc S

Neuro-oncology

2011 Volume 13, Issue 4, Page(s) 393–400

Abstract: Concomitant radiation therapy (RT) and temozolomide (TMZ) therapy after surgery is the standard treatment for glioblastoma multiforme (GBM). Radiation and chemotherapy can affect the immune system with implications on subsequent immune therapy. Therefore, ...

Abstract	Concomitant radiation therapy (RT) and temozolomide (TMZ) therapy after surgery is the standard treatment for glioblastoma multiforme (GBM). Radiation and chemotherapy can affect the immune system with implications on subsequent immune therapy. Therefore, we examined the phenotype and function of peripheral blood mononuclear cells in 25 patients with GBM prior to and 4 weeks after treatment with RT-TMZ using multicolor flow cytometry, as well as in vitro CD4(+) regulatory T cell (T(reg)) suppressor and dendritic cell maturation assays. RT-TMZ induced significant lymphopenia, with a decrease in total CD4(+) T cells, but did not significantly change monocyte counts. The proportion of functional T(reg) cells increased after treatment, whereas their absolute numbers remained stable. There was also a measurable decrease in the proportion of CD8(+)CD56(+) and absolute number of CD3(-)CD56(+) effector cells. Posttherapy monocytes retained the ability to mature into dendritic cells. Treatment with RT-TMZ is associated with changes in regulatory and effector peripheral blood mononuclear cells that tilt the balance towards an immune suppressive state. This shift can affect the outcome of immune therapy following RT-TMZ treatment and should be considered in the design of future combination therapy regimens.
MeSH term(s)	Adult ; Aged ; Antineoplastic Agents, Alkylating/therapeutic use ; Blood Cells/drug effects ; Blood Cells/immunology ; Blood Cells/radiation effects ; Brain Neoplasms/drug therapy ; Brain Neoplasms/immunology ; Brain Neoplasms/radiotherapy ; Combined Modality Therapy ; Dacarbazine/analogs & derivatives ; Dacarbazine/therapeutic use ; Dendritic Cells/drug effects ; Dendritic Cells/immunology ; Dendritic Cells/radiation effects ; Female ; Flow Cytometry ; Glioblastoma/drug therapy ; Glioblastoma/immunology ; Glioblastoma/radiotherapy ; Humans ; Lymphocyte Subsets ; Male ; Middle Aged ; Prognosis ; Radiotherapy Dosage ; T-Lymphocytes, Regulatory/drug effects ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/radiation effects ; Temozolomide ; Young Adult
Chemical Substances	Antineoplastic Agents, Alkylating ; Dacarbazine (7GR28W0FJI) ; Temozolomide (YF1K15M17Y)
Language	English
Publishing date	2011-02-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2028601-6
ISSN	1523-5866 ; 1522-8517
ISSN (online)	1523-5866
ISSN	1522-8517
DOI	10.1093/neuonc/noq204
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Zs.A 5307: Show issues

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Article: Induction of postsurgical tumor immunity and T-cell memory by a poorly immunogenic tumor.

Zhang, Peisheng / Côté, Anik L / de Vries, Victor C / Usherwood, Edward J / Turk, Mary Jo

Cancer research

2007 Volume 67, Issue 13, Page(s) 6468–6476

Abstract: The generation of protective CD8 T-cell memory against tumor-expressed self-antigens is an important but elusive goal of cancer immunotherapy. The possibility that a progressive, poorly immunogenic tumor can induce T-cell memory against self-antigens has ...

Abstract	The generation of protective CD8 T-cell memory against tumor-expressed self-antigens is an important but elusive goal of cancer immunotherapy. The possibility that a progressive, poorly immunogenic tumor can induce T-cell memory against self-antigens has not previously been studied. Herein, we report that growth of the poorly immunogenic B16 melanoma in the absence of regulatory T cells (T(reg)) generates CD8 T-cell responses that develop into functional memory after the tumor has been surgically excised. Tumor-primed memory T cells recognized melanocyte differentiation antigens TRP-2/DCT and gp100 and persisted for as long as 5 months following surgical tumor excision. Phenotypic analysis showed that these cells develop into both central and effector memory T-cell subsets, which produce IFN-gamma and interleukin-2 on reencounter with antigen. Most importantly, tumor-primed memory T cells mediated the rejection of intradermal and systemically disseminated challenge tumors given 30 to 60 days following surgery. Tumor-excised mice also developed autoimmune vitiligo, showing that T(reg) cells prevent tissue-specific autoimmunity in tumor-bearing hosts. This study establishes that T(reg) depletion in tumor-bearing hosts drives the natural development of protective T-cell memory. Generating such responses may aid in the clinical management of tumor recurrence and metastasis following surgery.
MeSH term(s)	Animals ; Autoimmune Diseases/immunology ; CD4-Positive T-Lymphocytes/metabolism ; Cytokines/metabolism ; Immunologic Memory ; Immunotherapy/methods ; Interferon-gamma/metabolism ; Interleukin-2/metabolism ; Male ; Melanoma, Experimental/immunology ; Melanoma, Experimental/pathology ; Mice ; Mice, Inbred C57BL ; Postoperative Period ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Vitiligo/immunology
Chemical Substances	Cytokines ; Interleukin-2 ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2007-07-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-07-1264
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Article ; Online: Gene expression profile of peripheral blood lymphocytes from renal cell carcinoma patients treated with IL-2, interferon-α and dendritic cell vaccine.

Wolf, Benita / Schwarzer, Adrian / Côté, Anik L / Hampton, Thomas H / Schwaab, Thomas / Huarte, Eduardo / Tomlinson, Craig R / Gui, Jiang / Fisher, Jan L / Fadul, Camilo E / Hamilton, Joshua W / Ernstoff, Marc S

PloS one

2012 Volume 7, Issue 12, Page(s) e50221

Abstract: Lymphocytes are a key component of the immune system and their differentiation and function are directly influenced by cancer. We examined peripheral blood lymphocyte (PBL) gene expression as a biomarker of illness and treatment effect using the ... ...

Abstract	Lymphocytes are a key component of the immune system and their differentiation and function are directly influenced by cancer. We examined peripheral blood lymphocyte (PBL) gene expression as a biomarker of illness and treatment effect using the Affymetrix Human Gene ST1 platform in patients with metastatic renal cell carcinoma (mRCC) who received combined treatment with IL-2, interferon-?-2a and dendritic cell vaccine. We examined gene expression, cytokine levels in patient serum and lymphocyte subsets as determined by flow cytometry (FCM). Pre-treatment PBLs from patients with mRCC exhibit a gene expression profile and serum cytokine profile consistent with inflammation and proliferation not found in healthy donors (HD). PBL gene expression from patients with mRCC showed increased mRNA of genes involved with T-cell and T(REG)-cell activation pathways, which was also reflected in lymphocyte subset distribution. Overall, PBL gene expression post-treatment (POST) was not significantly different than pre-treatment (PRE). Nevertheless, treatment related changes in gene expression (post-treatment minus pre-treatment) revealed an increased expression of T-cell and B-cell receptor signaling pathways in responding (R) patients compared to non-responding (NR) patients. In addition, we observed down-regulation of T(REG)-cell pathways post-treatment in R vs. NR patients. While exploratory in nature, this study supports the hypothesis that enhanced inflammatory cytotoxic pathways coupled with blunting of the regulatory pathways is necessary for effective anti-cancer activity associated with immune therapy. This type of analysis can potentially identify additional immune therapeutic targets in patients with mRCC.
MeSH term(s)	Cancer Vaccines/therapeutic use ; Carcinoma, Renal Cell/blood ; Carcinoma, Renal Cell/genetics ; Carcinoma, Renal Cell/therapy ; Cluster Analysis ; Cytokines/blood ; Dendritic Cells/immunology ; Female ; Flow Cytometry ; Gene Expression Profiling ; Humans ; Interferon-alpha/therapeutic use ; Interleukin-2/therapeutic use ; Kidney Neoplasms/blood ; Kidney Neoplasms/genetics ; Kidney Neoplasms/therapy ; Lymphocyte Subsets ; Lymphocytes/metabolism ; Male ; Middle Aged ; Oligonucleotide Array Sequence Analysis ; Real-Time Polymerase Chain Reaction
Chemical Substances	Cancer Vaccines ; Cytokines ; Interferon-alpha ; Interleukin-2
Language	English
Publishing date	2012-12-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0050221
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Article ; Online: Autoimmune melanocyte destruction is required for robust CD8+ memory T cell responses to mouse melanoma.

Byrne, Katelyn T / Côté, Anik L / Zhang, Peisheng / Steinberg, Shannon M / Guo, Yanxia / Allie, Rameeza / Zhang, Weijun / Ernstoff, Marc S / Usherwood, Edward J / Turk, Mary Jo

The Journal of clinical investigation

2011 Volume 121, Issue 5, Page(s) 1797–1809

Abstract: A link between autoimmunity and improved antitumor immunity has long been recognized, although the exact mechanistic relationship between these two phenomena remains unclear. In the present study we have found that vitiligo, the autoimmune destruction of ...

Abstract	A link between autoimmunity and improved antitumor immunity has long been recognized, although the exact mechanistic relationship between these two phenomena remains unclear. In the present study we have found that vitiligo, the autoimmune destruction of melanocytes, generates self antigen required for mounting persistent and protective memory CD8+ T cell responses to melanoma. Vitiligo developed in approximately 60% of mice that were depleted of regulatory CD4+ T cells and then subjected to surgical excision of large established B16 melanomas. Mice with vitiligo generated 10-fold larger populations of CD8+ memory T cells specific for shared melanoma/melanocyte antigens. CD8+ T cells in mice with vitiligo acquired phenotypic and functional characteristics of effector memory, suggesting that they were supported by ongoing antigen stimulation. Such responses were not generated in melanocyte-deficient mice, indicating a requirement for melanocyte destruction in maintaining CD8+ T cell immunity to melanoma. Vitiligo-associated memory CD8+ T cells provided durable tumor protection, were capable of mounting a rapid recall response to melanoma, and did not demonstrate phenotypic or functional signs of exhaustion even after many months of exposure to antigen. This work establishes melanocyte destruction as a key determinant of lasting melanoma-reactive immune responses, thus illustrating that immune-mediated destruction of normal tissues can perpetuate adaptive immune responses to cancer.
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/cytology ; Cytokines/metabolism ; Enzyme-Linked Immunosorbent Assay/methods ; Homeostasis ; Immunologic Memory ; Interferon-gamma/metabolism ; Melanocytes/cytology ; Melanoma/metabolism ; Melanoma, Experimental ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Skin Neoplasms/metabolism ; Vitiligo/metabolism
Chemical Substances	Cytokines ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2011-04-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI44849
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Article ; Online: Stimulation of the glucocorticoid-induced TNF receptor family-related receptor on CD8 T cells induces protective and high-avidity T cell responses to tumor-specific antigens.

Côté, Anik L / Zhang, Peisheng / O'Sullivan, Jeremy A / Jacobs, Valerie L / Clemis, Carli R / Sakaguchi, Shimon / Guevara-Patiño, José A / Turk, Mary Jo

Journal of immunology (Baltimore, Md. : 1950)

2010 Volume 186, Issue 1, Page(s) 275–283

Abstract: Treatment of tumor-bearing mice with a stimulatory Ab to glucocorticoid-induced TNFR family-related receptor (GITR) has previously been shown to elicit protective T cell responses against poorly immunogenic tumors. However, the role of GITR stimulation ... ...

Abstract	Treatment of tumor-bearing mice with a stimulatory Ab to glucocorticoid-induced TNFR family-related receptor (GITR) has previously been shown to elicit protective T cell responses against poorly immunogenic tumors. However, the role of GITR stimulation on CD8 T cells and the nature of tumor rejection Ags have yet to be determined. In this study, we show that a stimulatory mAb to GITR (clone DTA-1) acts directly on CD8 T cells, but not on CD4(+)CD25(+) regulatory T (T(reg)) cells, in B16 tumor-bearing mice to induce concomitant immunity against secondary B16 tumors, as well as protective memory following surgical excision of the primary tumor. Melanoma growth itself induced GITR expression on tumor-specific CD8 T cells, providing a mechanism whereby these cells may respond to stimulatory anti-GITR. Unexpectedly, in contrast to T(reg) cell depletion therapy with anti-CD4, GITR stimulation induced very weak CD8 T cell responses to melanocyte differentiation Ags expressed by the tumor, and did not induce autoimmune vitiligo. Accordingly, GITR-stimulated hosts that were primed with B16 melanoma rejected B16, but not the unrelated JBRH melanoma, indicating that tumor rejection Ags are tumor-specific rather than shared. In support of this, we show that GITR stimulation induces CD8 T cell responses to a tumor-specific Ag, and that these responses are of higher functional avidity compared with those induced by T(reg) cell depletion. We conclude that stimulation of GITR on effector CD8 T cells results in high-avidity T cell responses to tumor-specific Ags, thereby inducing potent antitumor immunity in the absence of autoimmunity.
MeSH term(s)	Animals ; Antigens, Neoplasm/immunology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/pathology ; Cell Adhesion/immunology ; Cell Line, Tumor ; Epitopes, T-Lymphocyte/immunology ; Female ; Glucocorticoid-Induced TNFR-Related Protein ; Lymphocyte Activation/immunology ; Lymphocyte Depletion ; Male ; Melanoma, Experimental/immunology ; Melanoma, Experimental/metabolism ; Melanoma, Experimental/prevention & control ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Receptors, Nerve Growth Factor/deficiency ; Receptors, Nerve Growth Factor/immunology ; Receptors, Nerve Growth Factor/metabolism ; Receptors, Tumor Necrosis Factor/deficiency ; Receptors, Tumor Necrosis Factor/immunology ; Receptors, Tumor Necrosis Factor/metabolism ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Antigens, Neoplasm ; Epitopes, T-Lymphocyte ; Glucocorticoid-Induced TNFR-Related Protein ; Receptors, Nerve Growth Factor ; Receptors, Tumor Necrosis Factor ; Tnfrsf18 protein, mouse
Language	English
Publishing date	2010-11-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1001308
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